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Defining cell intrinsic and extrinsic regulators of ferroptosis in pancreatic cancer

定义胰腺癌铁死亡的细胞内在和外在调节因子

基本信息

批准号：
10679812
负责人：
Heather Marie Giza
金额：
$ 4.08万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-02 至 2025-05-01
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679812
关键词：
Address Affect Alanine Apoptosis Biochemical Cancer Biology Cancer Etiology Cell Culture Techniques Cell Death Cell Death Induction Cells Cessation of life Chemoresistance Clinic Clinical Research Collaborations Combination Drug Therapy Culture Techniques Cysteine Cysteine Metabolism Pathway Cystine Cytolysis Dependence Diagnosis Diffuse Disease Drops Equilibrium Event Exhibits Extracellular Matrix Future Genetic Glutathione Goals Growth Human Cell Line Immune Immunotherapy In Vitro Individual Iron Link Lipid Peroxides Literature Malignant Neoplasms Malignant neoplasm of pancreas Membrane Metabolic Metabolism Michigan Modeling Mouse Cell Line Mus Nature Osmolar Concentration Osmosis Osmotic Pressure Oxidation-Reduction Oxidative Stress Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Proline Publications Regulation Research Resistance Resources Role Scheme Signal Transduction Stress Survival Rate System Taurine Testing Therapeutic United States Universities cancer cell cell type combat density experience extracellular in vivo insight interest metabolomics monolayer mortality novel therapeutic intervention pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic neoplasm pharmacologic pressure programs response scale up therapeutic target therapy resistant three dimensional cell culture treatment strategy tumor

项目摘要

Project Summary Pancreatic cancer, most commonly diagnosed as pancreatic ductal adenocarcinoma (PDAC), is amongst the top three leading causes of cancer death in the United States. These tumors are notoriously resistant to apoptosis and richly populated by stromal and immune cells that create a therapy-resistant microenvironment. Immunotherapy shows no benefit to patient survival, and despite advances in combinational chemotherapy the 5-year survival rate sits around 11%. Therefore, investigating alternative forms of cell death represents a unique strategy for targeting PDAC. Ferroptosis is a recently described form of cell death distinct from apoptosis. It is dependent on an accumulation of lipid peroxides, generated by free labile iron, resulting in osmotic cell lysis. Targeting ferroptosis can potently induce cell death in cultured PDAC cells. Yet, in PDAC tumors in mice, triggering ferroptosis has a modest response with distinct cases of intrinsic and acquired resistance currently limiting its therapeutic utility. It is therefore urgent that we address the gap between the in vitro and in vivo responses for future clinical studies. In pursuit of this, I am taking a reductionist approach to distill the mechanisms that regulate ferroptosis by osmotic and reductive-oxidative (redox) forces. Mechanistically, it is known that ferroptosis requires osmotic pressure to induce cell lysis, but this fact is not well studied within the current growing literature on ferroptosis in cancer. We hypothesize that cell death via ferroptosis requires an imbalance of redox metabolism and sufficient osmotic pressure, to which PDAC cells are particularly vulnerable. AIM I studies the biochemical dependencies between osmolarity and redox metabolism. AIM II distinguishes changes in the external osmotic pressure from the cellular biochemical adaptations, scaling up from monolayer to 3D culture techniques. Together, these aims investigate whether ferroptotic cell death can be simplified to a balance of redox and osmotic pressure. The overall goals of this study are to outline the boundary of these parameters and explore their application for targeting ferroptosis in PDAC.

项目摘要胰腺癌，最常见的诊断为胰腺导管腺癌(PDAC)，是在美国，癌症死亡的前三大原因之一。这些肿瘤臭名昭著抵抗细胞凋亡，并由大量的基质细胞和免疫细胞填充，从而产生治疗抵抗微环境。免疫疗法对患者的生存没有任何好处，尽管联合治疗取得了进展化疗5年存活率约为11%。因此，研究其他形式的细胞死亡代表了以PDAC为目标的独特战略。铁下垂是最近描述的一种独特的细胞死亡形式。来自于细胞凋亡。它依赖于由游离态铁产生的过氧化脂质的积累，从而导致渗透性细胞裂解。靶向铁下垂可以有效地诱导培养的PDAC细胞死亡。然而，在PDAC中在小鼠中，引发铁性下垂的肿瘤对先天性和获得性下垂有不同的反应耐药性目前限制了它的治疗作用。因此，当务之急是我们解决内部和外部之间的差距体外和体内的反应，为未来的临床研究。为了追求这一点，我采取了一种简化论的方法来提炼通过渗透和氧化还原(氧化还原)力量调节铁性下垂的机制。从机理上讲，铁下垂需要渗透压才能诱导细胞溶解，但事实并非如此。在目前不断增长的关于癌症中铁下垂的文献中得到了很好的研究。我们假设细胞死亡是通过铁性下垂需要氧化还原代谢的失衡和足够的渗透压，而PDAC细胞是特别脆弱的。目的研究渗透压与氧化还原之间的生化依赖关系。新陈代谢。目的II从细胞生化角度区分外渗压的变化改编，从单层到3D培养技术。总之，这些目标调查是否铁性细胞死亡可以简化为氧化还原和渗透压的平衡。这个项目的总体目标是研究目的是勾勒出这些参数的界限，并探索它们在靶向下垂方面的应用。 PDAC。